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J Biol Chem, Vol. 274, Issue 41, 29549-29557, October 8, 1999

Regulation of Acidification and Apoptosis by SHP-1 and Bcl-2

Muthusamy Thangaraju, Kamal Sharma, Brian Leber^**, David W. Andrews^**, Shi-Hsiang Shen^¶¶, and Coimbatore B. Srikant

From the  Fraser Laboratories, Department of Medicine, McGill University and Royal Victoria Hospital, Montreal, Quebec, H3A 1A1, Departments of ^** Biochemistry and  Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, L8N 325, and the ^¶¶ Pharmaceutical Sector, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec, H4P 2R2 Canada

Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells. Fas ligation also induces acidification-dependent apoptosis in a manner requiring the presence of SHP-1 at the membrane. Moreover, we have recently reported that SHP-1 is required not only for acidification, but also for apoptotic events that follow acidification (Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., and Srikant, C. B. (1999) Cancer Res. 59, 1649-1654). Here we show that ectopically expressed SHP-1 was predominantly membrane-associated and amplified the cytotoxic signaling initiated upon SST receptor activation and Fas ligation. The catalytically inactive mutant of SHP-1 (SHP-1C455S) abolished the ability of the SST agonists to signal apoptosis by preventing the recruitment of wild type SHP-1 to the membrane. Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST-induced apoptosis upstream of acidification by inhibiting p53-dependent induction of Bax as well as by raising the resting pH_i and attenuating SST-induced decrease in pH_i. By contrast, Bcl-2 failed to prevent apoptosis triggered by direct acidification. These data demonstrate that (i) membrane-associated SHP-1 is required for receptor-mediated cytotoxic signaling that causes intracellular acidification and apoptosis, and (ii) Bcl-2 acts distal to SHP-1 and p53 to prevent SST-induced acidification but cannot inhibit the apoptotic events that ensue intracellular acidification.

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